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B T Poll-The

Publications and source records attributed to B T Poll-The.

At least 73 records · Page 4Linked to original sources
PubMed1998

Simultaneous analysis of plasma free fatty acids and their 3-hydroxy analogs in fatty acid beta-oxidation disorders.

We present a new derivatization procedure for the simultaneous gas chromatographic-mass spectrometric analysis of free fatty acids and 3-hydroxyfatty acids in plasma. Derivatization of target compounds involved trifluoroacetylation of hydroxyl groups and tert-butyldimethylsilylation of the carboxyl groups. This new derivatization procedure had the advantage of allowing the complete baseline separation of free fatty acids and 3-hydroxyfatty acids while the superior gas chromatographic and mass spectrometric properties of tert-butyldimethylsilyl derivatives remained unchanged, permitting a sensitive analysis of the target compounds. Thirty-nine plasma samples from control subjects and patients with known defects of mitochondrial fatty acid beta-oxidation were analyzed. A characteristic increase of long-chain 3-hydroxyfatty acids was observed for all of the long-chain 3-hydroxyacyl-CoA dehydrogenase-deficient and mitochondrial trifunctional protein-deficient plasma samples. For medium-chain acyl-CoA dehydrogenase deficiency and very-long-chain acyl-CoA dehydrogenase deficiency, decenoic and tetradecenoic acids, respectively, were the main abnormal fatty acids, whereas the multiple acyl-CoA dehydrogenase-deficient patients showed variable increases of these unusual intermediates. The results showed that this selective and sensitive method is a powerful tool in the diagnosis and monitoring of mitochondrial fatty acid beta-oxidation disorders.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1997

Asymptomatic and late-onset ornithine transcarbamylase deficiency caused by a A208T mutation: clinical, biochemical and DNA analyses in a four-generation family.

We describe a 4-generation family in which a previously healthy 10-year-old boy died of late-onset ornithine transcarbamylase (OTC) deficiency. Pedigree analysis and allopurinol loading tests in female relatives were not informative. A missense mutation (A208T) in the OTC gene was detected in the deceased patient and in several clinically healthy male and female relatives, the oldest male being 97 years old. OTC deficiency was established in autopsy liver tissue of the propositus and liver biopsy samples of his sister, mother, and a maternal uncle. The males had 4% and 6% residual activity, respectively, the females 58% and 67%, respectively. The observed relation between the mutation and the decreased OTC activity in liver tissue of these subjects suggests that the mutation is a deleterious one. Late-onset, "mild" OTC deficiency can have a fatal or a favorable outcome. The disease can segregate undetected in families.

Adult↗
PubMed1997

Abnormal glutathione conjugation in patients with tyrosinaemia type I.

Previous studies have suggested that tyrosinaemia type I may be associated with reduced glutathione availability due to conjugation of tyrosinaemia-associated reactive intermediates with glutathione. In the present study, the glutathione/ glutathione S-transferase system of two tyrosinaemia patients and three healthy controls were characterized by administering the racemic sedative drug bromisoval, a probe drug for assessing glutathione conjugation activity in vivo. Furthermore, concentrations of glutathione and glutathione S-transferase class alpha (GSTA) isoenzymes as well as the glutathione S-transferase class mu phenotype were assessed in the blood of six tyrosinaemia patients. The excretion of bromisoval mercapturates in healthy children was comparable to that observed in healthy adults. Tyrosinaemia patients were found to have a very high urinary recovery of bromisoval mercapturates (> or = 60% of the dose compared to about 30% for healthy, age-matched children and adults), which could be attributed mainly to a higher urinary excretion of the mercapturate derived from S-bromisoval. Healthy children and adults predominantly excrete the (R)-bromisoval mercapturate. The differences in amount excreted as well as in stereoselectivity of the urinary excretion of bromisoval mercapturates in tyrosinaemia patients are possibly related to an increased activity of specific glutathione S-transferase isoenzymes. Plasma glutathione and blood cell glutathione disulphide concentrations in tyrosinaemia patients were normal. Low blood cell glutathione concentrations were in general found only in two patients with a poor clinical condition. These results indicate that, in contrast to previous suggestions, reduced glutathione availability is not a generalized problem in (stabilized) tyrosinaemia patients.

Adult↗
PubMed1997

In vivo stable isotope studies in three patients affected with mitochondrial fatty acid oxidation disorders: limited diagnostic use of 1-13C fatty acid breath test using bolus technique.

The in vivo oxidation of fatty acids (FA) of different chain length was investigated in three patients with documented mitochondrial FA oxidation disorders: one patient with mild multiple acyl-CoA dehydrogenase deficiency (MADM), one with medium chain acyl-CoA dehydrogenase deficiency (MCAD), and one with carnitine palmitoyltransferase I deficiency (CPT I). Breath tests were performed after oral administration of 1-13C butyric. 1-13C octanoic, and 1-13C palmitic acids. 13C/12C ratio in the expired oxidative end product CO2 was measured. The cumulative 13C elimination was calculated and expressed as a percentage of the administered dose. In the MADM patient the influence of carnitine therapy (or deprivation) on the utilization of 1-13C palmitic acid was also examined. In the MCAD and CPT I patients, the 1-13C butyric, 1-13C octanoic and 1-13C palmitic acids in vivo oxidation were similar to five healthy controls. In the MADM patient, the oxidation of 1-13C butyric and 1-13C octanoic acids were normal, whereas the metabolism of 1-13C palmitic acid ranged from 33% of 66% of controls. In this patient the serum carnitine level decreased from 60 to 27 mumol/l without carnitine supplementation. Clinically there was mild hypotonia. 1-13C palmitic acid oxidation compared to controls was 50%. After 2 further weeks of carnitine deprivation the serum carnitine was 10-15 mumol/l. Clinically he was very hypotonic and had a large liver. 1-13C Palmitic acid oxidation was 33%. After 6 weeks of readministration of carnitine (L-carnitine 100 mg/kg/day p.o.) the serum carnitine was 60 mumol/l and the patient was in good clinical condition. 1-13C palmitic acid oxidation was 66% compared to controls. Our study implies that this simple fatty acid breath test is not of diagnostic use for detection of enzymatic defects in FA oxidation disorders. The carnitine dependent 1-13C palmitic acid oxidation indicates that this test might be of some value in cases with primary or secondary carnitine deficiencies.

Acyl-CoA Dehydrogenase↗
PubMed1996

Non-rhizomelic and rhizomelic chondrodysplasia punctata within a single complementation group.

Several patients have been described recently who suffer from a non-rhizomelic type of chondrodysplasia punctata (CDP), but who show all the biochemical abnormalities characteristic of the rhizomelic form of chondrodysplasia punctata (RCDP), a peroxisomal disorder. We have used protease protection experiments and microinjection of reporter-protein-encoding expression plasmids to show that peroxisomal thiolase fails to be imported into peroxisomes in cells from non-rhizomelic CDP patients, as has already been found in cells from classical RCDP patients. Furthermore, complementation analysis after somatic cell fusion indicates that the non-rhizomelic CDP patients are impaired in the same gene as classical RCDP patients. We conclude that defects in a single gene can give rise to both clinical phenotypes.

Acetyl-CoA C-Acetyltransferase↗
PubMed1996

Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients with a pyruvate dehydrogenase complex deficiency.

Most of the mutations causing deficiency of the pyruvate dehydrogenase (PDH) complex are in the X-linked E1 alpha gene. We have developed a rapid screening method for the detection of mutations in this gene using reverse transcription of total RNA, polymerase chain reaction amplification of the whole coding region of the gene and single-strand conformation polymorphism (SSCP) analysis. With this method, we studied eight patients with a PDH complex deficiency, using cultured fibroblasts. In all patients, aberrant SSCP patterns were found and, after sequencing of the corresponding fragments, we were able to identify six new mutations and two mutations already described previously. The mutations are point mutations leading to amino acid substitutions (5) and direct repeat insertions (3). The presence of the mutations was confirmed in genomic fibroblast DNA. The 4 female patients were shown to carry both a normal and a mutated E1 alpha gene.

Base Sequence↗
PubMed1996

Hereditary tyrosinemia type 1: novel missense, nonsense and splice consensus mutations in the human fumarylacetoacetate hydrolase gene; variability of the genotype-phenotype relationship.

The complete fumarylacetoacetate hydrolase (FAH) genotype of probands of thirteen unrelated families with hereditary tyrosinemia type 1 (HT 1) was established. The screening was performed by analysis of exons 2-14 of the FAH gene by using the polymerase chain reaction (PCR) and of the mRNA by reverse transcription/PCR. Nine different mutations were identified, of which six are novel. Three mutations involve consensus sequences for correct splicing, viz. IVS 6-1 (g-t), IVS 7-1 (g-a) and IVS 12 + 5 (g-a). Two missense mutations (C193R and G369V) and three nonsense mutations (R237X, E357X and E364X) were found. One silent mutation N232N was associated with the skipping of exon 8 from the FAH mRNA. Analysis of the effect of the respective mutations on the FAH mRNA showed a strong reduction of FAH mRNA levels in association with the nonsense mutations, and normal levels with the missense mutations. The splice consensus mutations give deletions of complete or small parts of exon sequences from the FAH mRNA. Data suggest a founder effect for several of the mutations, with a frequency for both the IVS 6-1 (g-t) and IVS 12 + 5 (g-a) mutations of approximately 30% in the HT 1 probands. No strict correlation between genotype and phenotype, i.e. the acute, subacute or chronic form of HT 1, was evident.

Alleles↗
PubMed1996

Plasma total odd-chain fatty acids in the monitoring of disorders of propionate, methylmalonate and biotin metabolism.

Total plasma odd-numbered long-chain fatty acids were analysed in patients with methylmalonic acidaemia (vitamin B12-responsive and unresponsive), combined methylmalonic acidaemia/homocystinuria (CblC), propionic acidaemia (both neonatal-onset and late-onset), biotinidase deficiency and holocarboxylase synthase deficiency, as well as in hospital controls. Total odd-numbered long-chain fatty acids (C15:0, C17:1 and C17:0) were expressed as a percentage of total C12-C20 fatty acids. Control values were 0.72% +/- 0.31% (n = 12). Normalization of the percentage of odd-chain fatty acids occurred in all vitamin-responsive patients, following the institution of vitamin treatment. In general the neonatal-onset propionic acidaemia and B12-unresponsive methylmalonic acidaemia patients had the highest plasma odd-chain fatty acid concentrations, which correlated with the clinical condition but not with the urinary excretion of methylcitrate or methylmalonate. Plasma odd-chain fatty acid concentrations and methylmalonate excretions in CblC patients reacted very well to vitamin B12 treatment, but with no clinical response. Measurement of plasma odd-chain fatty acids is of no value for the monitoring of defects of biotin metabolism.

Adolescent↗
PubMed1996

Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: clinical and biochemical considerations.

Three patients with propionic acidemia were studied. The first patient was diagnosed at the age of 9 mo, 3 mo after he developed hypotonia and choreoathetoid movements after an upper respiratory tract infection. The second patient was diagnosed at the age of 1.5 mo when she became comatose after nasogastric tube feeding because of failure to thrive. The third patient was diagnosed at the age of 5 d when she presented with feeding difficulties, hypotonia, and respiratory insufficiency. Magnetic resonance imaging (MRI) of the brain in all patients revealed delayed myelination and some cerebral atrophy. In the patient with choreoathetosis, MRI showed bilateral abnormalities in the signal intensity of the putamen and caudate nuclei. MRI of the other two patients showed normal basal ganglia. Proton magnetic resonance spectroscopy (1H MRS) from a voxel located in the basal ganglia revealed a decrease in N-acetylaspartate and myo-inositol peaks and an elevation of glutamine/ glutamate. The presence of spectroscopic abnormalities in a stable metabolic condition, in particular the rise in glutamine/ glutamate, indicates that the metabolic balance on cerebral parenchymal level is less optimal than estimated from biochemical analysis of urine, plasma, or cerebrospinal fluid.

Age of Onset↗
PubMed1995

Clinical approach to inherited peroxisomal disorders.

At least 21 genetic disorders have now been found that are linked to peroxisomal dysfunction. Whatever the genetic defect might be, peroxisomal disorders should be considered in various clinical conditions, dependent on the age of onset. The prototype of peroxisomal disorders is represented by 'classical' Zellweger syndrome (ZS) which is the most severe disorder combining all the characteristic symptoms. ZS is characterized by the association of errors of morphogenesis, severe neurological dysfunction, neurosensory defects, regressive changes, hepatodigestive involvement with failure to thrive, usually early death, and absence of recognizable liver peroxisomes. Other peroxisomal disorders (pseudo-Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), pseudo-neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata (RCDP), and hyperpipecolic acidaemia) share some of these symptoms, but with varying organ involvement, severity of dysfunction, and duration of survival. The diagnosis should not cause difficulty when all the characteristic manifestations are present. Depending on the main presenting sign, peroxisomal disorders in neonates should be suspected in two categories of circumstances: polymalformative syndrome with craniofacial dysmorphism, and severe neurological dysfunction. During the first 6 months of life, the predominant symptoms may be hepatomegaly, prolonged jaundice, liver failure, anorexia, vomiting and diarrhoea leading to failure to thrive resembling a malabsorption syndrome; severe psychomotor retardation, hearing loss and ocular abnormalities become evident. Beyond 4 years of age, behavioural changes, intellectual deterioration, visual impairment and gait abnormalities may be the presenting symptoms. Independently of the clinical symptoms and age of onset, most peroxisomal disorders described so far can be clinically screened by recordings of electroretinogram, visual-evoked responses, and brain auditory-evoked responses, which are almost always abnormal. Nine of the 17 peroxisomal disorders with neurological involvement are associated with an accumulation of very long-chain fatty acids (VLCFA), which suggests that assay of plasma VLCFA should be used as a primary test. However, assays of plasma phytanic acid and plasma/urine bile acid intermediates should also be performed in view of the recent reports of atypical chondrodysplasia variants (without rhizomelic shortening) and isolated trihydroxycholestanoic aciduria. The differential diagnoses in various clinical conditions and age periods are discussed.

Child↗
PubMed1995

Peroxisome mosaicism in the livers of peroxisomal deficiency patients.

Peroxisomal deficiency disorders, which are genetically transmitted, are assumed to be expressed in all cells, and the use of cultured skin fibroblasts for diagnosis and research is based on this assumption. We describe three patients with clinical, biochemical, and microscopic evidence of a peroxisomal disorder. However, their liver displays mosaicism, i.e., parenchymal cells with peroxisomes are adjacent to cells without peroxisomes. Ten percent (volume), 8%, and less than 1% of the parenchyma possessed peroxisomes that can be identified in immunocytochemical tests for six matrix and membrane proteins performed by light and electron microscopy. In the bulk of the parenchyma, catalase is localized in the cytoplasm, and in such cells no peroxisomes are evident by electron microscopy and immunolabeling for the 43-kd peroxisomal membrane protein (PMP) in two patients; in the third case, peroxisomal membrane ghosts are present. Immunoblots of peroxisomal beta-oxidation enzymes show a pattern similar to that from patients with a generalized peroxisomal deficiency. In contrast to the clinical and biochemical signs of peroxisomal dysfunction and hepatic histopathology, cultured fibroblasts from two patients demonstrate normal peroxisomal functions, including very-long-chain fatty acid oxidation and plasmalogen synthesis.

Bile Acids and Salts↗